bi236 wk 8 lecture gastrointestinal system

BI236 Wk 8 Lecture Gastrointestinal System Physiology of the GI System Acid-related disorders

1. Gastric ulcer [GU] 2. Duodenal ulcer [DU] 3. Gastroesophageal reflux disease [GERD or GORD] 4. Functional dyspepsia 5. Non-steroidal anti-inflammatory drug (NSAID) associated duodenal ulcer 6. H. Pylori - negative peptic ulcers

I. Peptic Ulcer Definition

A circumscribed ulceration of the mucous membrane of the stomach or the duodenum Peptic ulcer is generally used to describe both Gastric (Stomach) Ulcer and Duodenal (Duodenum) Ulcer

Formation

•

•

Symp

1. 2. 3. 4. 5. 6.

Symp

1. 2. 3.

2004KK

penetrates through muscularis mucosa usually occurs in areas exposed to Acid and Pepsin

toms (general) Burning or gnawing pain between the bottomPain relief on consumption of food but returnsPain in the early hours of the morning Loss of appetite with weight gain or weight loNausea or vomiting Frequent burping or bloating

toms (serious condition) Sharp, sudden, persistent stomach pain Black or Bloody stools

Bloody vomit or vomit that looks like coffee g

Require immediate medical attention and

C BI236 Gastro-intestinal System

of the breastbone and the navel a few hours later

ss

rounds

hospitalization

of 22

Causes / Risk Factors

1. Helicobacter pylori infection is now considered the primary cause of ulcers the bacterium located in the mucosa along with acid secretion can damage the

tissue of the stomach and duodenal causing inflammation and ulcers 2. Acid and pepsin

believed to contribute to the formation of ulcers 3. NonSteroidal Anti-Inflammatory Drugs

via its inhibition action on postaglandins alters the buffering capacity of the mucosa

reduces blood flow to mucosa and cell repair 4. Alcohol consumption

Alcohol irritates the stomach lining and increases stomach acid output 5. Smoking

smoking increases acid secretion slows the healing of existing ulcers and contributes to ulcer recurrence

6. Stress Physical stress such as trauma, major surgery

7. Family history of ulcers Stomach’s protective Mechanism Ulcers appear when the protective lining (mucosa, submucosa) of the gastrointestinal tract is eroded The stomach can protect itself by producing:

• a lubricant-like mucus that coats and shields stomach mucosa / tissues • bicarbonate that neutralizes and breaks down digestive fluids into less harmful

substances Blood circulation in the lining of the stomach and cell renewal and repair help protect the stomach Gastric Ulcer

Duod

2004KK

Lesions that appear on the inner wall of thestomach Majority occur along the lesser curvature ofthe stomach i.e. at the junction of the fundic mucosa and the antral mucosa Tend to develop later in age (>40) Associated with normal or diminished acid secretion Pain occur intermittently or followed by food consumption Surrounding gastritis is usually presented

enal Ulcer It is a circumscribed defect in the epithelium of the duodenum Over 90% are found in the duodenal bulb or cap most ulcers are small (< 2 cm) in diameter

C BI236 Gastro-intestinal System of 22

Non-steroidal anti-inflammatory drug (NSAID) associated duodenal ulcer NSAIDs

• damage the gastric mucosa • cause inflammation • cause erosions and ulceration • approximately 25% experience dyspeptic symptoms but do not have an ulcer • dose should be reduced to a minimum when prescribed to ulcer patients who require

them H. pylori - negative peptic ulcers Only a very small proportion of patients suffering from peptic ulcers not due to NSAIDs do not have H. pylori detected

• duodenal ulcer less than 5% • benign gastric ulcer less than 10%

Factors controlling the regulation of gastric secretion 1. 10th cranial nerve (vagus)

• the vagus nerve merges with the autonomic nervous system • controls the action of the muscles in the digestive tract • the secretion of the digestive glands

2. Hormones

Hormones of the endocrine system exert an indirect or regulatory control of body activities

a. Gastrin • stimulates production of gastric acid / pepsin • stimulates gastrointestinal motility • is strongly influenced by the release of histamine

b. Enterogastrine • inhibits gastric secretion and motility

3. Histamine High concentration in GI mucosa, skin, lungs, CNS

• contraction of bronchial smooth muscle: wheezing of asthma • increase in vascular permeability : " runny " nose of hay fever • dilation of capillaries: clogged nasal passage • stimulation of nerve endings: tingling sensation • gastric acid secretion

Gastric Acid Secretion Basal Acid Output (BAO) Unstimulated level of acid secretion:

• Greatest at night ( 11 - 1 pm ) and least in the morning Under stimulation (food)

• the level of acid secretion rises as much as 10 times the basal rate

2004KKC BI236 Gastro-intestinal System of 22

Food Stimulated Gastric Acid Secretion Just before --- during --- shortly after ----> sharp rise in acid output

KKCKKC--BI236 BI236 Gastrointestinal SystemGastrointestinal System

Food Stimulated Gastric Acid Secretion

GASTRINGASTRIN ACETYL CHOLINEACETYL CHOLINE

HISTAMINEHISTAMINE

HClHCl

MM

GGH2

CNSFOOD

G Cell G Cell EnterochromaffinEnterochromaffin--like celllike cellECLECL

parietal

G G –– G Cell/G Cell/GastrinGastrin receptorreceptor– MuscarinicMuscarinic receptorreceptor

Peptic Ulcer Treatment Goals

1. Symptom relief 2. Ulcer Healing 3. Prevention of relapses (Eradication of H pylori)

Therapeutic Agents

1. Antacids 2. Gastric Acid Inhibitors 3. Drugs enhancing Mucosal Resistance (Cytoprotection)


1. Antacids Act by neutralising gastric acid and reducing the acid load emptied into the duodenum Characteristics of an ideal antacid:

• have a high buffering capacity • be long acting • be as little absorbed as possible • no local gastrointestinal or systemic side effects

Undesirable side effects:

• aspiration pneumonia • hypermagnesaemia • increase plasma aluminium • alkalosis • diarrhoea • large sodium load

a. Alkaline Salts

• neutralise or partially neutralise gastric acidity • are compared quantitatively in terms of their Acid Neutralising Capacity (ANC) defined as

the number of mmol of 1 M HCl that can be brought to pH 3.5 in 15 minutes • the neutralisation process is fast

Sodium hydrogen carbonate (baking soda) Calcium carbonate Magnesium Hydroxide (Milk of Magnesia)

b. Colloidal Antacids

• Insoluble salts with buffering properties • Buffer gastric acidity at pH 4 • May protect surface of an ulcer by mechanical coating

Aluminium hydroxide

causes constipation drug interactions stimulates mucus secretion

Aluminium hydroxide gel Aluminium hydroxide gel with magnesium hydroxide Magnesium Trisilicate Magnesium hydroxide & Aluminium oxide hydrates (Magnesia & Alumina)

Surface-active agents(anti-flatulants) Are usually included in proprietary preparations

• to disperse foam • to diminish gastroesophageal reflux (GERD) • to relief dyspeptic symptoms

Charcoal(activated) Simethicone (Dimethicone) Polysiloxane (methyl)


2. Gastric Acid Inhibitors

a. Anticholinergic Agents Modest ability to reduce secretion of gastric acid Oxyphencyclimine HCl Daricon®

Propantheline Bromide Pro-banthine® Pirenzepin DiHCl Bisvanil®

• More selective action on gastric muscosa M1 receptor • Free from usual anticholinergic side effects • interfers with Gastrin secretion in addition to acid secretion

b. Gastrin Receptor Antagonist

Block gastrin receptors Proglumide Milid®

c. Histamine H2 receptor Antagonist

H2-receptor Antagonists inhibit gastric acid secretion by competing with histamine for the H2-receptors on the parietal cell

Only block gastric secretion elicted by muscarinic agonist or gastrin via Enterochromaffin-like (ECL) cells stimulation Cimetidine Tagamet® Ranitidine Zantac® Famotidine Pepcidine® Nizatidine Axid®

Limitations of H2 receptor Antagonists

1. Achieve ~ 60% acid blockage only because cannot completely block induction of acid secretion via gastrin or cholinergic stimuli (direct stimulation of parietal cell)

2. Usually short-acting (~ 4 h) 3. Effective in inhibiting acid secretion under basal conditions, less effective after

ingestion of a meal 4. Tolerance develops in a considerable percentage of patients [high doses have to

be used]

d. Hydrogen Potassium ATPase Inhibitor (Proton pump inhibitor) H+/K+-ATPase represents the final step in the secretory process of gastric acid Normal activity is as follows:


Hydrogen Potassium ATPase Inhibitor (Proton pump inhibitor)

HH++

HH22 receptorreceptor

cAMPcAMP

HistamineHistamineHH22 receptor Antagonistreceptor Antagonist

Ca Ca 2+2+

AchAchreceptorreceptor

a. receptor-mediated stimulation of the parietal cell leads to activation of the proton pump

b. exchange of cytoplasmic H+ for luminal K+ ions occurs

c. this results in acid secretion Anticholinergic

H+ HH++HH++

AcetylcholineAcetylcholine

KK++

KK++KK++

CanaliculusCanaliculus

[[ClCl--]]

GastrinGastrinreceptorreceptor


Mechanism of PPIs

are inactive prodrug derivatives of benzimidazoles at acidic pH they are converted to the active sulfenamide cation the reactive intermediate then combines covalently with the SH group of the H+/K+

ATPase forming a complex acid secretion from the parietal cell is inhibited

Unlike H2 antagonist, PPIs can achieve over 90% acid inhibition because this is the final site in acid secretion induced by histamine, gastrin and acetylcholine dependent pathway

Omeprazole Losec® Esomeprazole Nexium ® Lansoprazole Prevacid® Pantoprazole Pantoloc® Rabeprazole Pariet ®

3. Drugs enhancing Mucosal Resistance (Cytoprotection) Mucosal resistance depends on:

• mucosal blood flow • stimulation of mucus and hydrogen carbonate secretion • mucosal cell turn-over and cellular restitution

a. Postaglandins

PGE2 and methyl analogues • reduce gastric acid secretion [antisecretory effects on the parietal (oxyntic) cell] • improves the protective mucus layer • provide endogeneous neutralising factor: HCO3

- • causes diarrhoea Misoprostol Cytotec®

b. Sucralfate

Polysulphated basic aluminium salt of sucrose • act principally by accretion with the proteinaceous base of ulcer i.e. form a

mechanical barrier between the ulcerand the acid and pepsin • stimulate local prostaglandins synthesis • adsorbed pepsin and bile salts Sucralfate Ulsanic®

c. Collodial Bismuth Salt

• little neutralising effect • bismuth oxide plus gastric acid form a protective layer over the ulcer surface • effective in eradicating the bacteria Helicobacter pylori

Bismuth aluminate, subgallate, subnitrate Bismuth subcitrate (Tripotassium di-citratobismuthate TDB)

Bismuth subcitrate De-nol® Bismuth subsalicylate Pepto-Bismol®


Helicobacter pylori D

The Prevalence of H. pylori infection

ranges and meansranges and means

1 2 T

1

2

2

Campylobacter pylori [ renamed in 1989 ] • a spiral multiflagellate gram-negative

bacterium • clonizes the mucous on the lumial surface

of the gastric epithelium • produces a urease enzyme allowing its survival

in the acidic environment • triggers both local and systemic immune

responses • causes gastritis and is a putative contributor to

peptic ulcer disease, gastric lymphoma, and adenocarcinoma

• detected in antral samples of majority of patients (70-90%) with duodenal and

gastric ulcers

iagnostic Test for H pylori


Duodenal UlcerDuodenal Ulcer

Nonspecific gastritisNonspecific gastritis

Gastric ulcerGastric ulcer

NonulcerNonulcer dyspepsiadyspepsia

Gastric carcinomaGastric carcinoma

NormalNormal

10 20 30 40 50 60 70 80 90 100 %10 20 30 40 50 60 70 80 90 100 %00

. Rapid urease test [CLO test] a change in the pH indicator dye colour from yellow to pink confirms a positive result . Urea breath tests [UBTs]

a breath sample is taken before and 30 minutes after drinking a 13/14 C-labelled urea solution

reatment schedules Triple therapy

• most effective eradication therapy regimens reported to date • offer remarkably high incidence of eradication • reduced incidence of side effects • improved patient compliance • with twice daily dosing regimens

involving PPIs achieve the level of eradication in one week the Ranitidine regimen requires two weeks

. Regimen involving Proton pump inhibitors (PPI) a. Proton pump inhibitors [1-2 tab bd] b. Metronidazole [400mg bd]

PLUS either

Amoxycillin [1g bd ] or Clarithromycin [250-500mg bd]

for 7 days

. Regimen involving H2 antagonist Ranitidine a. Ranitidine [300mg OD] b. Metronidazole [500mg tds] c. Amoxycillin [750mg tds] for 14 days


II. Constipation Definition

• is a decrease in the frequency of stool or difficulty in the formation or passage of stool

• the passage of hard stools less frequently than the patient's own normal pattern

Causes of Constipation

a. Not enough fiber in the diet The bulk and soft texture of fiber help prevent hard, dry stools that are difficult to pass

b. Inadequate fluid intake Liquids like water and juice add fluid to the colon and bulk to stools, making bowel movements softer and easier to pass

c. Lack of exercise d. Medications

analgesics (especially narcotics) antacids that contain aluminum and calcium antihypertensive medications (calcium channel blockers) antispasmodics antidepressants iron supplements

e. Changes in life or routine Pregnancy: hormonal changes or because the heavy uterus compresses the

intestine Aging: a slower metabolism results in less intestinal activity and muscle tone Traveling:because normal diet and daily routines are disrupted

f. Abuse of laxatives Over time, laxatives can damage nerve cells in the colon and interfere with the colon's natural ability to contract

g. Ignoring the urge to have a bowel movement may eventually stop feeling the urge, which can lead to constipation

h. Specific diseases Neurological disorders

o multiple sclerosis o Parkinson's disease o stroke o spinal cord injuries

Metabolic and endocrine conditions o diabetes o underactive or overactive thyroid gland

Systemic disorders o lupus o scleroderma

i. Problems with the colon and rectum Intestinal obstruction, tumors, colorectal stricture or cancer can compress, squeeze, or narrow the intestine and rectum and cause constipation

j. Problems with intestinal function (chronic idiopathic constipation)


Treatment A. Non-pharmacological approach

a. Eat a well-balanced, high-fiber diet that includes bran, whole grains, fresh fruits, and vegetables

b. Drink plenty of water/fruit juices c. Exercise regularly d. Allow ample time for undisturbed visits to the toilet e. Do not ignore the urge to have a bowel movement

B. Pharmacological Approach Laxatives Substances that promote the passage of stool Types of laxatives

1. Bulk-forming laxatives Increasing faecal mass/volume which stimulates peristalsis

a. Psyllium hydrophilic mucilloid Metamucil b. Ispaghula husk Isogel, Fybrogel c. Methylcellulose d. Sterculia Normacol

2. Stimulant laxative Increase intestinal motility (peristalsis) and reducing net reabsorption of electrolyte & water, but often cause abdominal pain

a. Bisacodyl Ducolax b. Senna Senokot c. Glycerol Glycerine suppositories d. Sodium Picosulphate Picolax e. Docusate Sodium* Norgalax

[Dioctyl sodium sulfosuccinate]

3. Faecal softeners Lubricate and soften impacted faeces and promote a bowel movement

a. Docusate Sodium b. Liquid paraffin Agarol Emulsion

limit the effectiveness of other medicines and inhibit absorption of fat soluble vitamins (A, D, E, and K)

4. Osmotic laxative

Act by retaining fluid in the bowel by osmosis a. Lactulose (galactose + fructose) Duphalac

(also for hepatic encephalopathy) b. Macrogol (polyethylene glycols) Forlax c. Magnesium salts d. Sodium Phosphate/citrate Enema Fleet, Micolax


III. Diarrhoea Definition Repeated bowel movement (Three or more times per day) with semi-liquid or watery stools and sometimes excess gas Resulted from conditions leading to:

• More rapid than normal movement of bowel contents through the intestine • Delayed normal reabsorption of water in the large intestine • Secretion of excess water into the bowel

Causes The presence of irritating or toxic substances in the intestine brought about by:

1. Phychologic Factors Stress Anxiety

2. An existing chronic diseae Endocrine abnormalities IBS

3. Food Poisoning [Loose stool] over indulgence of food or alcohol ingestion of toxic foods, adulterated or overripe food food allergy [intolerance of lactose (found in cow milk)

4. Medication Laxatives Antibiotics

5. Infectious agents a. Virus [Gastroenteritis]

caused by Rotavirus, Hepatitis virus b. Bacteria [Bacterial Dysentery]

i. Non-invasive enterotoxigenic bacteria Adhere to intestinal absorptive cell and secrete enterotoxins that alter fluid electrolyte transport system causing mass loss of Cl-, Na+ and water

• Escherichia Coli • Salmonella enteritidis • Cholera

ii. Invasive bacteria

Can invade the epithelium, secrete enterotoxins and cause inflammation and tissue damage leading to blood loss

• Shigella • E. Coli • Salmonella typhimurium [Typhoid] • Campylobacter jejuni


c. Protozoa [Protozoal dysentery] Consumption of water contaminated with protozoa such as Entamoeba histolytica Amoebiasis Giardia lamblia Giardiasis

Treatment of Acute diarrhoea a. Rehydration therapy

Correction of dehydration is the first priority (particular important for infants/babies) Oral Rehydration Therapy(WHO)

Na+ 90 mmole/litre K+ 20 mmole/litre Cl- 80 mmole/litre Citrate ion 30 mmole/litre Glucose 111 mmole/litre

b. Drugs that alter gastrointestinal motility

Opiate/Opiate-like antidiarrhoeal agents Act on µ-opiate receptors/5-HT receptors Enhance absorption and by modulating acetylcholine release, reduce peristaltic activity and increase transit time Morphine Codeine Diphenoxylate (plus Atropine sulphate in Lomotil® ) Loperamide

c. Fluid adsorbents Bulking action improve stool consistency Abdorption of toxins

Kaoline (plus pectin) Dioctahedral Smectite Smecta®

d. Fluid absorbents Bulk-forming agents act by absorbing water Bran Ispaghula husk Methylcellulose Sterculia

e. Antibacterials

Chloera / Salmonella typhimurium Tetracycline/Chloramphenicol

Shigella Ampicillin Penbritin® Campylobacter Erythromycin/Ciprofloxacin Protozoa [Amoeba, Giardia] Metronidazole Flagyl® Tinidazole Fasigyn®


IV. Irritable bowel syndrome (IBS) Definition can be defined as a combination of abdominal pain or discomfort and altered bowel habit in the form of altered stool frequency or altered stool form Diagnostic Criteria for IBS (Revised Rome Criteria) At least 12 weeks or more, which need not be consecutive, in the preceding 12 months of abdominal pain or discomfort that has 2 of 3 features:

1. Relieved with defecation and/or 2. Onset associated with a change in frequency of stool and/or 3. Onset associated with a change in form (appearance) of stool

Symptoms

• Abnormal stool frequency (for more than 3 bowel movements per day and fewer than 3 bowel movements per week)

• Abnormal stool form (lumpy/hard or loose/watery stool) • Abnormal stool passage (straining, urgency, or feeling of incomplete evacuation) • Passage of white mucus • Bloating or feeling of abdominal distension • Relief of abdominal pain or discomfort transiently after defecation and abdominal

bloating • Extra-intestinal conditions: such as fibromyalgia, sexual dysfunction, urinary

symptoms, and certain psychiatric disorders • Abdominal pain or discomfort commonly occurs in the left lower quadrant, but

can be found anywhere in the abdomen Patients with IBS have traditionally been described as being

1. "constipation predominant," 2. "diarrhoea predominant," 3. "alternators" [having an alternating pattern of constipation and diarrhoea]

These 3 variants of IBS is represented approximately equally in the overall IBS population Prevalence approximately between 10% and 20% of the population.

• Less than 50 years of age 15% - 20% • Greater than 50 years of age 10% -12% • No particular country or geographic area seems to definitively stand out as

having a higher or lower prevalence of IBS. • IBS does seem to be more prevalent in women

The female to male ratio for individuals with IBS not to seek care is 2:1 seeking care is 4:1


Pathophysiology of IBS The pathophysiology of IBS remains incompletely understood 1. Concept of altered gut motility

Altered motility of the colon and small bowel can be demonstrated in patients with IBS, but

is seen as one of many epiphenomena associated with the disorder, as opposed to being a cause of the disorder itself

no pathognomonic pattern of gut dysmotility can be identified specifically with IBS very poor correlation between IBS symptomatology and the presence of

alterations in gastrointestinal motility drugs (antispasmodic and prokinetic )that alter gastrointestinal motility alone have

not been shown to be of any significant benefit in relieving IBS symptoms 2. Concept of "brain-gut axis" ("visceral" hypersensitivity)

IBS patients feel discomfort at lower levels of balloon inflation in the rectum and lower bowel than do normal controls

IBS patients have differential responses in the anterior cingulate cortex and other areas of the brain when stimulated with rectal or sigmoid colon distention, compared with controls

neuropeptides such as motolin, gastrin, peptide Y, cholecystokinin, serotonin that are involved in the regulation of both gastrointestinal motility and sensation in the gut might play an important role in altered processing of neural sensation

3. Role of Serotonin

revolutionized the practice of psychiatry [selective serotonin reuptake inhibitor (SSRI) acting on 5-HT1 and 5-HT2 receptors exclusively in the central nervous system]

more than 90% of the body serotonin is found in the gut and not in the central nervous system

modulation of serotonin action on 5-HT3 and 5-HT4 receptors contained in the gut could influence IBS and other functional bowel symptoms

other neurotransmitters such as Cholecystokinin antagonist and various neurokinin antagonists could also be potential candidates


Treatment of IBS A. Diet and Lifestyle Modification

Cognitive behavioral therapy, hypnosis, and relaxation therapy have all been effectively applied to the treatment of IBS, particularly in patients with severe symptomatology

B. Symptom-Targeted Treatment

1. Antispasmodic and prokinetic drugs like metoclopramide and cisapride

2. Bulking agents could be helpful for IBS-related constipation

3. Antidirrhoeal agent loperamide, helpful in terms of relieving IBS-related diarrhoea

4. Tricyclic antidepressants (desipramine and paroxetine) for the treatment

of IBS-related abdominal pain or discomfort

5. 5-HT3 Antagonists [Treatment of IBS with diarrhoea] Antagonism of the 5-HT3 receptor causes significant slowing in colonic transit and a decrease in visceral sensation

Alosetron 1.0 mg b.d. Lotronex Restricted for women with severe diarrhoea-predominant Irritable Bowel Syndrome Adverse effect : ischemic colitis (1 in 350 ) Cilansetron, (phase 3 trials )

6. 5-HT4 Agonists [Treatment of IBS with constipation] 5-HT4 receptor in the gut (stimulation) is

associated with intestinal peristaltic reflexes intestinal rates of colonic transit decrease in the activity of visceral afferent neurons

5-HT4 Agonists should

increase the rate of intestinal colonic transit reduce the firing rate of colonic visceral afferent nerves reduce visceral sensitivity

Tegaserod (partial agonist ) Zelnorm

for the short-term treatment of women suffering from IBS with constipation

has not been shown to be helpful for men

increases the number of bowel movements decrease bloating reduce abdominal pain or discomfort, and improve stool frequency and consistency major side effect is diarrhoea ( bowel movements normalizing after

about 2 weeks of use)


V. Nausea and Vomiting are biological defense mechanisms

• The major physiological function of emesis (vomiting) is to remove toxic or harmful substances from the body after ingestion

• Emesis is multi-factorial in origin Emetic stimuli include:

1. Motion sickness and vestibular disturbances Meniere's disease and viral labyrinthitis

2. Surgery Post-operative side effects 3. Pregnancy Morning sickness 4. Drugs Side effects of opioid analgesics 5. Radiation Chemotherapy-induced 6. Disgusting sights, smells or memories

The vomiting reflex The process of emesis can be classified into three phases:

1. Nausea • an unpleasant sensation that immediately proceeds vomiting • a cold sweat, pallor, salivation, a noticeable disinterest in the

surroundings, loss of gastric tone, duodenal contractions and the reflux of intestinal contents into the stomach

2. Retching

• follows nausea • comprises laboured spasmodic respiratory movements against a

closed glottis with contractions of the abdominal muscles, chest wall and diaphragm without any expulsion of gastric contents

• can occur without vomiting but normally generates the pressure gradient that leads to vomiting

3. Vomiting

• caused by the powerful sustained contraction of the abdominal and chest wall musculature

• accompanied by the descent of the diaphragm and the opening of the gastric cardia

• a reflex activity that is not under voluntary control • results in the rapid and forceful evacuation of stomach contents up

to and out of the mouth


The Vomiting Reflex Pathway Si Ma

200

te of Action of Antiemetics

in Classes of Anti-emetic drugs

Pharmacological Class Muscarinic receptor Antagonist (Anti-cholinergic)

ScSc

Histamine H1 – receptor Antagonist (Anti-histamine)

CiDi

Dopamine D2-receptor antagonists (Gastroprokinetic)

MPrHa

Cannabinoid NaCorticosteroid

DeM

5HT3-receptor antagonist

GTr

Histamine analogue BeNeurokinin-1 antagonist Vo

ApEz

4KKC BI236 Gastro-intestinal System

Neurotransmitters involved in Emesis

1. Acetylcholine 2. Dopamine 3. Histamine 4. 5-Hydroxytryptamine (5HT) 5. Noradrenaline, adrenaline 6. Substance P

antagonists of receptors for each ofthese transmitters have anti-emetic effects

oonnmetoclobx

etraoptaforelo

The management of nausea and vomiting Important medical issues to beaddressed: 1. Identification and elimination of

the underlying cause if possible 2. Control of the symptoms if it is

not possible to eliminate the underlying cause

3. Correction of electrolyte, fluid or nutritional deficiencies

Drug polamine (L-hyoscine) poderm TTS arizine Cyclizine

enhydrate Promethazine oclopramide Domperidonehlorperazine peridol ilone amethasone hylprednisolone nisetron Ondansetronisetron Dolasetron histine pitant pitant pitant

of 22

Liver Diseases Viral Hepatitis an inflammation of the liver caused by viruses Types of Hepatitis

a. Hepatitis A (HAV) • also referred to as "infectious hepatitis" because of mode of transmission of

illness • hepatitis A virus (HAV) transmitted via the fecal-oral route

[i.e. spread through food, water, and stool, especially where unsanitary conditions allow water or food to be contaminated by human sewage ]

• an acute illness that never develops into a chronic form of liver infection

b. Hepatitis B (HBV) • referred to as "serum hepatitis," because it was thought that the only way

hepatitis B virus (HBV) could spread was through blood or serum contamination

• Not Observable in 30% of persons • it can spread by sexual contact • the transfer of blood or serum through

needle sticks blood transfusions hemodialysis childbirth

• 6-10% of these patients develop chronic hepatitis B infection (infection lasting more than six months)

c. Hepatitis C (HCV)

• previously referred to as "non-A, non-B hepatitis," • the hepatitis C virus (HCV) is believed to be spread by blood transfusion,

hemodialysis, and needle sticks • approximately 90% of transfusion-associated hepatitis is caused by hepatitis

C • 80% of persons have no signs or symptoms • 50-70% of these patients develop chronic hepatitis C infection • patients with chronic hepatitis C infection can continue to infect others

d. Hepatitis D (HDV)

• occurs only in people who are already infected with hepatitis B • severe acute disease • high risk of severe chronic liver disease

e. Hepatitis E (HEV)

• most outbreaks associated with fecally contaminated drinking water • minimal person-to-person transmission • Illness severity increases with age


Viral Hepatitis Overview Types of Hepatitis

A B C D E

Source of Virus

faeces Blood/Blood derived body fluid

Blood/Blood derived body fluid

Blood/Blood derived body fluid

faeces

Route of Transmission

fecal-oral Percutaneous per mucosal

Percutaneous per mucosal

Percutaneous per mucosal

fecal-oral

Type of Infectious

Acute Chronic Chronic Chronic Acute

Prevention Pre/post exposure immunization

Pre/post exposure immunization

Blood donor screening; risk behavior modification

Pre/post exposure immunization risk behavior modification

Ensure drinking water

Symptoms Most individuals who contract hepatitis B and C have no symptoms Most common are:

• loss of appetite • nausea & vomiting • low grade fever • haedache • fatigue • diarrhoea • abdominal pain

Less common symptoms include

dark urine light-colored stools fever jaundice (yellowing of the skin and white portion of the eyes)

Patients with

• Hepatitis A do not develop chronic infections • Chronic hepatitis B or C can be infected for many years and have a lifelong increased

risk of developing

liver cirrhosis and/or liver cancer

50% of patients with chronic hepatitis B will die of cirrhosis or liver cancer Chronic hepatitis C causes liver failure


I. Prophylaxis of Hepatitis [Active immunisation] a. Hepatitis A

Havrix 1440 ELISA units / ml Age > 19 years a single dose and then boosters at 6 & 12 months later Age < 19 half dose

Vaqta 50u / ml Age > 18 years a single dose and then booster at 6 -12 months later Age < 18 years half dose

b. Hepatitis B

• vaccine is the best protection • Infants born to HBV-infected mothers should be given HBIG (hepatitis B immune

globulin) and vaccine within 12 hours after birth Engerix-B 20ug/ml

3 doses at 0, 1, 6 months Age < 16 years half normal dose

HB-Vax II 10ug / ml 3 doses at 0, 1, 2-12 months Age < 19 years half the normal dose

Booster every 5 years II. Treatment of Hepatitis Hepatitis A & E Both types usually resolve on their own over several weeks Hepatitis B Acute hepatitis B usually resolves on its own For chronic hepatitis B:

a. Interferon Alpha interferon

• interferon alfa-2b Intron A • interferon alfa-2a Roferon

Peginterferon (Pegylated interferon)

• peginterferon alfa-2b Peg-Intron b. Nucleoside reverse transcriptase inhibitors NRTIs

Lamivudine Zeffix • safe and rarely causes side effects • not a permanent or complete cure • keeps the virus in check for only as long as it is taken • when treatment stops, HBV DNA and ALT levels usually rebound • patients develop lamivudine-resistant HBV

c. Selective inhibitor of viral polymerase and reverse transcriptase

Adefovir dipivoxil Hepsera • as effective as Lamivudine • does not develop viral resistance


Hepatitis C

Sustained Virologic Response means that the HCV virus cannot be seen in the patient’s blood 6 months or more after completing hepatitis C therapy

Viral load

hepatitis C virus ribonucleic acid level or hepatitis C RNA level

ALT level Alanine aminotransferase

A. Monotherapy: Interferon alone

1. Interferon alfa-2a Roferon-A 2. Interferon alpha 2b Intron-A 3. Interferon alfacon-1 Infergen

B. Combination therapy: Interferon plus oral antiviral drug Ribavirin 1. Interferon alpha 2b + Ribavirin Interferon 3 MU three times per week Ribavirin in two divided doses daily

1,000 mg for < 75 kg 1,200 mg for > 75 kg

2. Pegylated alpha 2b interferon + Ribavirin Peginterferon alpha 2b 1.5 ug/kg weekly

Ribavirin 800mg qd 3. Pegylated alpha 2a interferon (Pegasys) + Ribavirin Peginterferon alpha 2a 180 ug/kg weekly

• Combination therapy achieve better result than interferon monotherapy • Ribavirin alone is ineffective

Treatment should continue for 48 weeks for those who are HCV RNA negative after 24 weeks Decision to continue or withdraw therapy based on virological response at 24 weeks


Liver Cirrhosis characterized by widespread nodules in the liver combined with fibrosis

1. distortion of the normal liver architecture interferes with blood flow through the liver

2. lead to an inability of the liver to perform its normal biochemical functions Cirrhosis results from damage to liver cells from

• toxins • inflammation • metabolic derangements

Damaged and dead liver cells are replaced by fibrous tissue which leads to fibrosis (scarring)

Liver cells regenerate in an abnormal pattern primarily forming nodules surrounded by fibrous tissue

Causes of Cirrhosis

1. Alcoholic liver disease most common cause

2. Chronic viral hepatitis B, C and D 3. Inherited metabolic diseases

(e. g. hemochromatosis, Wilson disease) 4. Chronic bile duct diseases

(e. g. primary biliary cirrhosis) 5. Parasitic infections

(e. g. schistosomiasis) 6. Long term exposure to toxins or drugs

Cancer of the Liver

1. Metastatic Cancer of the Liver cancers that originate in other organs and spread to the liver via the bloodstream

2. Hepatocellular Carcinoma cancers that originate in the liver due to chronic liver disease 3. Cholangiocarcinoma cancers of the bile ducts


bi236 wk 8 lecture gastrointestinal system

Documents